A Humanized Monoclonal Antibody Specific for Invariant Natural Killer T (iNKT) Cells for In Vivo Depletion

Abstract

Invariant Natural Killer T (iNKT) cells are a subset of T cells recognizing glycolipid antigens presented by CD1d. Human iNKT cells express a conserved T cell receptor (TCR)-α chain (Vα24-Jα18) paired with a specific beta chain, Vβ11. The cells are both innate-like, with rapid cytokine release, and adaptive-like, including thymic positive selection. Over activation of iNKT cells can mediate tissue injury and inflammation in multiple organ systems and play a role in mediating the pathology associated with clinically important inflammatory diseases. At the same time, iNKT cell activation can play a role in protecting against infectious disease and cancer or modulate certain autoimmune diseases through its impact on both the innate and adaptive immune system. This suggests that approaches to cause iNKT cell reduction and/or depletion could treat inflammatory diseases while approaches to promote activation may have therapeutic potential in certain infections, cancer or autoimmune disease. This report summarizes the characterization of a humanized monoclonal depleting antibody (NKTT120) in the cynomolgus macaque. NKTT120 is being developed to treat iNKT mediated inflammation that is associated with chronic inflammatory conditions like sickle cell disease and asthma. NKTT120 binds to human iTCRs and to FCγRI and FCγRIII and has been shown to kill target cells in an ADCC assay at low concentrations consistent with the FCγR binding. iNKT cells were depleted within 24 hours in cynomolgus macaques, but T cell, B cell, and NK cell frequencies were unchanged. iNKT cell recovery was dose and time dependent. T cell dependent antigen responses were not impaired by NKTT120 mediated iNKT depletion as measured by response to KLH challenge. NKTT120 administration did not induce an inflammatory cytokine release at doses up to 10 mg/kg. These data support the use of NKTT120 as an intervention in inflammatory diseases where iNKT reduction or depletion could be beneficial.

The role of iNKT cells on the phenotypes of allergic airways in a mouse model

“…We have also demonstrated that the elimination of iNKT cells using NKT-14 was effective, and that it did not affect the total number of leukocytes in lung tissue, supporting the notion that NKT-14 is specific for iNKT cells [35, 44]. In this study, we show that targeting iNKT cells with NKT-14 also translated to an elimination of αGalCer induced AHR, further illustrating the specificity and impact of NKT-14.…”

“…Bedel et al showed that the genetic modifications in the B6.Jα18 −/− mice were not limited to the iNKT cells but had widespread consequences on the T cell population in general. In this context, it is important to note that NKT-14 is specific for iNKT cells but does not affect the type II NKT cells [44]. The possibility to use a specific agent like NKT-14 therapeutically to deplete a cell type in a model is significantly different from studying a model in which the cell type never existed due to a gene knockout.…”

Cellular therapy for sickle cell disease

“…A humanized iNKT cell depleting antibody, NKTT120, targets the invariant T cell receptor and has recently been developed for application in iNKT-mediated inflammatory conditions such as asthma and sickle cell disease [17]. This antibody has been tested in a Phase I clinical trial (NCT01783691), and early reports show that at the highest tested dose (0.3mg/kg), no dose limiting toxicities are seen and iNKT cells are depleted for a minimum of 28 days before recovery [18].…”

Emerging drugs for sickle cell anemia

“…Preclinical studies showed depletion of iNKT cells and no effect on other natural killer cells. The T cell antibody response was not impaired in reponse to a KLH challenge [66]. A phase I trial planned to enroll 21 patients with SCD is currently recruiting (NCT 01783691).…”